Antidepressant efficacy of Cb1 agonist Hu-210 in mice following chronic administration is not dependent on constitutive neurogenesis

Research has shown antidepressant/anxiolytic efficacy of acute cannabinoid treatment on preclinical tests. However, the behavioral effects of chronic cannabinoid administration in animal models of depression are still unknown. In the present study we have used the animal model of chronic administration of corticosterone in mice (35 μg/ml, 28days, oral ) in order to evaluate: a)the effect of chronic administration of the cannabinoid agonist HU-210 (25 μg/kg/day, i.p. 2weeks) in tests assessing anxiety- and depressive-like responses, and spatial short term memory; and b) the influence of constitutive neurogenesis on behavioral effects of HU-210, using a transgenic mouse in which ablation of glial fibrillary acidic protein (GFAP)-positive cells (thus eliminating adult neural progenitor cells) was induced by ganciclovir. Corticosterone-treated mice exhibited an anxiogenic response in the novelty-suppressed feeding (NSF, latency to feed=323.1±59.5 vs 137±14.3 seconds in control group; p< 0.01) and a depressive-like response in the sucrose preference test (>anhedonia>; %sucrose intake/total= 50.8±5.7 vs. 90.8±1.3 in control; p< 0.01). An impaired performance in the T-maze test (short-term spatial memory) was also shown in corticosterone-treated animals (%alternance= 49.7±2.7 vs 63.1±2.5 in control; p< 0.05). Chronic HU-210 reversed anxiety- (NSF, latency to feed= 174.5±30.8s; p< 0.01 vs corticosterone) and depressive-like (%sucrose=78.9±3.1%; p< 0.01 vs corticosterone) behaviors but not the impaired short term spatial memory. These effects of chronic HU-210 in the NSF (latency to feed=123.3±19.9s; p< 0.01 vs corticosterone) and sucrose (% sucrose= 78.8±1.8; p< 0.01 vs corticosterone) paradigms were still present in transgenic animals treated with chronic corticosterone. This is the first study demonstrating the anxiolytic and antidepressant actions of chronic HU-210 in a validated animal model of depression/anxiety. Our results in transgenic animals also indicate that constitutive neurogenesis might not be necessary for the behavioral effects of HU-210 in this animal model.